The long-term goal of this project is to translate results of basic neuroscience research into useful palliative and protective interventions for neurodegenerative disorders affecting motor and cognitive function. Progress towards understanding the pathogenesis of the response alterations complicating levodopa treatment of Parkinson's disease has continued. In patients with this disorder, apomorphine, a direct dopamine receptor agonist, was found to replicate the response changes underlying motor fluctuations and choreiform dyskinesias elicited by levodopa challenge, thus providing strong clinical support for earlier animal model observations that secondary modifications postsynaptic to the dopamine system account for the appearance of this disabling syndrome. Last year we reported that NMDA receptor antagonists ameliorate motor complications in MPTP lesioned primates as well as in 6-hydroxydopamine-lesioned rats. Now we find that co-therapy with certain drugs of this type can also block the appearance of these response alterations. Previous rodent model studies suggested that these glutamate antagonist effects were primarily mediated by NMDA receptors on striatal medium spiny neurons. It now appears that activation of cAMP-dependent protein kinase (PKA) signaling pathways linked to co-expressed dopaminergic receptors participates in the NMDA receptor up-regulation; current results suggest that increased tyrosine phosphorylation on both the NR1 and NR2B subunits underlies this functional change. The contribution of NMDA receptor supersensitivity to motor complications in parkinsonian patients has been further supported and an approach to treatment now discovered by findings of controlled studies showing that dextromethorphan and amantadine diminish these iatrogenic response alterations without compromising levodopa's anti- parkinsonian efficacy. Studies of apoptotic mechanisms in striatal spiny neurons have also begun to identify potential targets for novel pharmaceutical intervention. To characterize molecular mechanisms contributing to excitotoxic neuronal death, changes in striatal transcription factor binding activity were measured after quinolinic acid infusion. NFkB binding rapidly increased followed by the appearance of apoptotic stigmata. Both changes were inhibited by cycloheximide and by NFkB SN50, a selective blocker of NFkB nuclear translocation. NFkB involvement in the excitotoxin-induced apoptotic destruction of striatal neurons has prompted exploration of approaches to the selective inhibition of this factor. Related studies have found that metabotropic receptor stimulation augments the kainic acid-induced but attenuates the NMDA-induced apoptotic-like death of these neurons. In MPTP lesioned primates, robust neuroprotection has been obtained with a glutamate antagonist but not with a free radical scavenger.